The Mayo Clinic is a founding member of the Cooperative Family Registry (CFR), an NCI-supported consortium of six centers initiated in 1997 to establish a comprehensive collaborative infrastructure to facilitate interdlsciplinary studies of the genetics and epidemiology of colorectal cancer (CRC). Using common data collection protocols and core instruments, the CFR centers recruit CRC probands and their relatives. By the end of the current recruitment phase (July 2002), the CFR will have accrued data and biospecimens from 7,773 probands, 15,232 relatives (affected and unaffected), and more than 2000 unrelated controls, demonstrating the high level of productivity of the CFR as a whole. To fully realize the research potential of the CFR, we collectively propose the following specific alms in the next five years: focused recruitment of (1) high risk families and (2) minorities (African-American and Japanese); (3) systematic follow-up of CFR participants; (4) identification of all carriers of mutations in the DNA mismatch repair (MMR)genes; (5) maintain the CFR biospecimens repository; (6) maintain bioinformatics support activities; (7) establish a fresh frozen tissue repository utilizing the CFR infrastructure. Cost effective ascertainment of large numbers of high-risk families has been a strength of the Mayo CFR design. We have met and exceeded our original aims regarding recruitment of high-risk families and collection of tumor blocks. The Mayo group?s commitment to the CFR as a whole is evidenced by our leadership in writing two competitive supplements that supported registry-wide essential activities (MSI tumor testing and biospecimen processing), our collaborative research activities, and our active role in all CFR working groups. For this renewal, the Mayo CFR proposes to recruit 160 high-risk probands and their family members from the Mayo Clinic Rochester and 200 high-risk probands and their family members from the population-based Minnesota Cancer Surveillance System. We will identify 60 individuals from Mayo Clinic on whom we will collect fresh frozen CRC tissue and whose families will be recruited under the comprehensive data collection protocol. We will conduct systematic follow-up on all our originally studied families to enhance the capacity to correlate exposure histories, family histories, and molecular markers with clinic outcomes; we will provide biospecimens for MMR gene analysis; we will maintain the Mayo biospecimens and bioinformatics systems. We propose a pilot pilot ease-control study of the association of heterozygosity for alpha-l-antitrypsin deficiency alleles as a risk factor for mismatch repair-deficient CRC in smokers and non smokers. The Mayo CFR members are dedicated to advancing knowledge on colorectal cancer using the opportunities created by the CFR?s comprehensive collaborative structure, large numbers of participants, and its harmonious team of investigators.